ArticleProceedings of the National Academy of Sciences of the United States of America2024
Structural insights reveal interplay between LAG-3 homodimerization, ligand binding, and function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 33 citations in OpenAlex.
- Trends and hotspots in research related to tumor immune escape: bibliometric analysis and future perspectives.Frontiers in immunology · 2025Pooled it
- Clinical Impact of CTLA4 and LAG3 Single-Nucleotide Polymorphisms in Multiple Myeloma Patients Treated With BCMA CAR T-Cell Therapy.Hematological oncology · 2026Article
- LAG3 checkpoint function and its mechanism of action in therapeutic targeting.Nature reviews. Immunology · 2026Review
- The liver-secreted protein FGL1 restrains a subset of innate-like B cell responses via the receptor TACI.Immunity · 2026Article
- Immune implications and therapeutic opportunities of tumor glycosylation.Nature cancer · 2026Review
- T Cell Exhaustion in Cancer Immunotherapy: Heterogeneity, Mechanisms, and Therapeutic Opportunities.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Lymphocyte function inhibition and exhaustion in sepsis: mechanisms and applications.Frontiers in immunology · 2026Review
- Lymphocyte activation gene 3 in autoimmune disease: from molecular mechanisms to clinical applications.Frontiers in immunology · 2026Review
- Unraveling fibrinogen-like protein 1's role in immune regulation.Frontiers in immunology · 2026Review
- Clinical Impact of LAG3 Single-Nucleotide Polymorphism in DLBCL Treated with CAR-T Cell Therapy.International journal of molecular sciences · 2025Article
- New horizons in B-cell lymphoma immunotherapy: From immune checkpoints to precision medicine.Neoplasia (New York, N.Y.) · 2025Review
- Article
- Post-translational modifications of cancer immune checkpoints: mechanisms and therapeutic strategies.Molecular cancer · 2025Review
- Therapeutic potential of targeting LAG-3 in cancer.Journal for immunotherapy of cancer · 2025Review
- Exploring new frontiers in LAG-3 biology and therapeutics.Trends in pharmacological sciences · 2025Review
- One Step Ahead: Preventing Tumor Adaptation to Immune Therapy.American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting · 2025Review
- Dual role of interferon-gamma in the response of melanoma patients to immunotherapy with immune checkpoint inhibitors.Molecular cancer · 2025Review
- Post-translational modifications of immune checkpoints: unlocking new potentials in cancer immunotherapy.Experimental hematology & oncology · 2025Review
- LAG Time in the Era of Immunotherapy-New Molecular Insights Into the Immunosuppression Mechanism of Lymphocyte Activation Gene-3.Immunological reviews · 2025Review
- Advances in LAG3 cancer immunotherapeutics.Trends in cancer · 2025Review
Corrections and comments
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Authors and funding
17 authors at 4 institutions in 1 country.
Funding
Abstract
Lymphocyte activation gene-3 (LAG-3) is an inhibitory receptor expressed on activated T cells and an emerging immunotherapy target. Domain 1 (D1) of LAG-3, which has been purported to directly interact with major histocompatibility complex class II (MHCII) and fibrinogen-like protein 1 (FGL1), has been the major focus for the development of therapeutic antibodies that inhibit LAG-3 receptor-ligand interactions and restore T cell function. Here, we present a high-resolution structure of glycosylated mouse LAG-3 ectodomain, identifying that cis-homodimerization, mediated through a network of hydrophobic residues within domain 2 (D2), is critically required for LAG-3 function. Additionally, we found a previously unidentified key protein-glycan interaction in the dimer interface that affects the spatial orientation of the neighboring D1 domain. Mutation of LAG-3 D2 residues reduced dimer formation, dramatically abolished LAG-3 binding to both MHCII and FGL1 ligands, and consequentially inhibited the role of LAG-3 in suppressing T cell responses. Intriguingly, we showed that antibodies directed against D1, D2, and D3 domains are all capable of blocking LAG-3 dimer formation and MHCII and FGL-1 ligand binding, suggesting a potential allosteric model of LAG-3 function tightly regulated by dimerization. Furthermore, our work reveals unique epitopes, in addition to D1, that can be targeted for immunotherapy of cancer and other human diseases.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.